In this renewal project we propose to continue our research on the functions of the Sonic hedgehog (Shh)-Gli pathway in neural development during embryonic, perinatal and adult stages using the mouse as an experimental model. Specifically, we will study the role of Gli protein function in Nestin progenitors during mouse brain growth and patterning, focusing on their role in the neocortex. We will also investigate Shh-Gli function in neural stem cells, from both the embryonic neocortex and the postnatal and adult subventricular zone of the lateral ventricle. The results of our proposed research will help in understanding how this important signaling pathway regulates the growth and patterning of the brain, with special emphasis placed on the neocortex, a preeminent structure in human brain function. Our ongoing research on how progenitor cells respond to Shh-Gli function will help in understanding how the brain is formed, which will also lead to an understanding of the bases of a number of mental deficits. Indeed, our findings will likely shed light into the possible mental deficits that patients with viable forms of holoprosencephaly (a disease that can arise from defective SHH signaling) may display. In addition, the knowledge of how the SHH-GLI pathway affects brain precursors will help our understanding of how brain tumors arise, an area of research covered under a different, yet related, project in the laboratory.